Members of the steroid/thyroid receptor superfamily have been shown to be important for the regulation of target genes essential for cellular differentiation and development. In our laboratory, we have concentrated on the elucidation of physiological functions of COUP-TFs. A null mutation of the COUP-TFI gene in mice has been generated in our laboratory through the support of this grant. These animals display many defects in the peripheral and central nervous system (PNS and CNS). In the PNS, we have determined that differentiation of ganglia IX is compromised resulting in the apoptosis of neural crest derived superior ganglia (1). In addition, we observed defects in axon arborization and guidance. In the CNS, COUP-TFI mutation results in the malformation of cortical layers and hippocampus, defects in axon myelination and failure of corpus callosum and hippocampal commissures to cross the midline. Furthermore, we also detected defects in bone morphogenesis and development of the inner ear (see preliminary results). In the next grant period, we would like to determine the underlying mechanisms for these defects and identify the COUP-TFI target genes responsible. Finally, we would like to determine which signals regulate the expression of the COUP-TFI gene in a spatio- and temporal-specific manner. To achieve these goals, we propose the following three specific aims: 1. Characterization of the COUP-TFI mutant mice for cortical layer and axonal myelination defects; 2. Identification of signals regulating the COUP-TFI gene expression in transgenic animals; 3. Isolation and characterization of COUP-TFI target genes for rescue COUP-TFI phenotypes. It is expected that the understanding derived from this project will be relevant to the biology of development and differentiation. The proposed studies will also be pertinent to the development of more precise theories for the biochemical mechanism of action of hormones and their receptors.